Egyptian pediatric guidelines for the management of childhood venous thromboembolism: the adapted methodology: a limited resource country perspective

Abstract

Background

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Thrombosis is a major pediatric health problem with a spectrum of etiologies, clinical presentations, and morbidities. Establishing the diagnosis and treatment of pediatric thrombosis with different site-related presentations may be challenging. This article adapts the high-quality Clinical Practice Guidelines (CPGs) for pediatric thrombosis management to suit the Egyptian healthcare context.

Methods

The adapted ADAPTE methodology was used to identify the high-quality CPGs published between 2012 and 2023. An expert panel screened, reviewed, and assessed the CPGs and formulated the adapted consensus recommendations based on the best available evidence.

Results

The final CPG document provides consensus recommendations and implementation tools for managing thrombosis with different etiologies in children and adolescents in Egypt. There is no evidence to support strong recommendations for various management approaches.

Conclusions

In general, a complete clinical and radiological assessment and some laboratory tests are indicated at the initial diagnosis to confirm a thrombotic disorder and to further choose the type of workup required. Future research should report the outcome of this adapted guideline and include cost-analysis evaluations.

Adapted from source guidelines:

• 1. The University of Wisconsin Venous Thromboembolism Prophylaxis—Pediatric—Inpatient—Consensus Care Guideline, UWHealth 2023 [1].

• 2. Thrombophilia testing: A British Society for Haematology guideline. BSH 2022 [2].

• 3. Guidelines on the investigation, management, and prevention of venous thrombo-embolism in children. BSH 2011: Addendum BSH 2021 [3, 4].

• 4. BSH Guideline: Management of Thrombotic and Hemostatic Issues in Pediatric Malignancy, BSH 2018 [5].

• 5. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. ASH 2018 [6].

• 6. Antithrombotic Therapy in Neonates and Children. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. ACCP 2012 [7].

Introduction

Thrombosis is increasingly recognized in the pediatric age group, especially venous thromboembolism (VTE). However, recent studies showed increasing incidences of childhood thrombotic events due to improved diagnosis, increased survival of children with severe underlying diseases, and increased use of interventions such as central venous lines (CVL). Moreover, the diagnosis of VTE in hospitalized children increased from 34 to 58 cases per 10,000 in the United States from 2001 to 2007. The increased incidence of thrombosis was observed in all pediatric age categories; nevertheless, neonates, infants (< 2 years old), and adolescents have the greatest risk for VTE [8, 9]. Egyptian children who have more than one heterozygous mutation, even if weakly thrombophilic, are prone to developing significant thrombotic events either spontaneously or when exposed to minor risk factors [10].

No previous study for global incidence of pediatric VTE, but a few country-based studies. The majority of them focused on hospital-based populations. Longitudinal data from a population-based cohort study in Québec, QC, Canada, found a stable VTE incidence of 0.29 events per 10,000 person-years in children less than 18 years old over the 11-year study period ending in 2004 [11]. In Korea, the incidence was reported to be 3.27 per 10,000 admissions [12]. In Hong Kong, it was 0.074 per 10,000 children [13].

In Egypt, no previous studies have stood on the national epidemiology of pediatric VTE. While different recent standard guidelines for pediatric VTE from different international societies have been released, the clinical implications of such standard guidelines face diversity of challenges in Egypt. The financial constraints, the availability of well-trained specialized health care personnel, the demography, the variability and complexity of the genetic background in different areas in Egypt, and the availability of well-equipped tertiary hospitals that can handle such patients. All these mandate the adaptation of the standard guidelines for pediatric VTE to cop with these challenges and to secure the best available diagnostic and therapeutic chance for such patients.

Thrombosis is a serious disease that leads to mortality and morbidity. The mortality rate is about 2%. Morbidity includes lack of thrombus resolution in 50% of the patients, the development of post-thrombotic syndrome (PTS) in 9%, and recurrent thrombosis in 8.1% with an average follow-up period of 2.86 years [14].

Most of the venous thrombi in children are associated with clinical risk factors such as inheritance of prothrombotic defects, CVL insertion, cardiac disease, surgery, obesity, inflammatory conditions, immobility, medications such as asparaginase and estrogen-containing contraceptives, and cancer patients [15]. Also, there are some diseases with an increased tendency to thrombosis called acquired thrombophilia diseases, such as antiphospholipid syndrome (APS), paroxysmal nocturnal hemoglobinuria (PNH), myeloproliferative neoplasms (MPN), and the presence of a Janus Kinase 2 (JAK2) mutation in the absence of an MPN phenotype [2].

The inheritance of prothrombotic defects is called inherited thrombophilia diseases, which refers to genetic disorders of specific hemostatic proteins that include the factor V Leiden (FVL) variant (F5 G1691A), the prothrombin gene variant (F2 G20210A), protein C (PC) deficiency, protein S (PS) deficiency, and antithrombin (AT) deficiency. The homozygous or combined heterozygous inheritance of any of these prothrombotic genetic defects may lead to spontaneous VTE (unprovoked VTE), VTE with severity disproportionate to the stimulus (provoked VTE), recurrent thrombosis, or VTE at a young age. However, it is still a matter of debate whether it is useful to test for genetic thrombophilia defects in children with a first venous thrombotic event [16].

Cancer patients are at high risk of recurrent VTE; on one side, they are at high risk for anticoagulant-related bleeding, which is associated with high morbidity and resource use [17].

The mainstay of treatment for acute pediatric thrombosis is anticoagulation with heparins and/or vitamin K antagonists. The immediate goals of anticoagulation are to prevent the propagation of acute thrombosis, prevent embolization, and prevent secondary VTE. The duration of therapy is, therefore, predicated on the time-dependent risk of recurrent VTE. Unfortunately, there is limited data with which to accurately define the frequency of VTE recurrence and anticoagulation-associated adverse events in pediatric VTE [6]. Bleeding is the primary complication of anticoagulant therapy and is a risk for all anticoagulants, even when maintained within usual therapeutic ranges. Ironically, whereas unfractionated heparin and coumarin, the oldest and most widely used anticoagulants, have specific antidotes for their anticoagulant effect, many of the newer agents currently undergoing clinical evaluation do not have specific antidotes; thus, the best ways to reverse their actions remain to be determined [7].

The aim of this adapted clinical practice guideline (CPG) is to provide evidence-based recommendations to pediatricians and junior hematologists for the diagnosis, treatment, and prevention of thrombosis in pediatric age groups.

Materials and Methods

Most standard pediatric thrombosis guidelines are not directly applicable in certain entities due to specific aspects of the Egyptian healthcare system (e.g., resource constraints, limited access to specialized care, and local epidemiological issues). These hurdles strict application of standard guidelines, either due to an inadequate number of qualified treatment centers or medical health care providers. All these necessitated tailoring of the international guidelines by adaptation to apply to the health care providers.

The CPG adaptation project was part of the fourth wave of the Egyptian pediatric guidelines (EPG) national CPG projects [7, 18, 19]. This CPG was prepared to provide practical consensus recommendations for the management of thrombosis in children and adolescents in Egypt. The Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) Hematology Group included 17 members with recognized clinical and research expertise in pediatric hematology representing 9 tertiary research centers from different Egyptian governorates (Ain Shams University, Alexandria University, Armed Forces College of Medicine, Beni-Sueif University, Cairo University, Mansoura University, Minia University, National Research Center and Zagazig University) selected this topic as one of the high-priority health topics in Pediatric Hematology in Egypt [19].

Searching tools

A literature search of the relevant CPG using six web databases and libraries: Guidelines International Network Library and Registry (GIN), World Health Organization (WHO) Guidelines, National Institute for Clinical and Health Excellence (NICE) UK.http://www.nice.org.uk/guidance/, Scottish Intercollegiate Guidelines Network (SIGN) UK. http://www.sign.ac.uk/guidelines/, ECRI Guidelines Trust (USA). https://guidelines.ecri.org/, DynaMed (Summaries: Guidelines and Resources).

Also, the bibliographic electronic database PubMed was searched in April 2023 for relevant source original CPG retrieval. The following search terms were used: “pediatric thrombosis,” “childhood thrombosis”, “thromboembolism,” “venous and arterial thrombosis,” “Thrombophilia,” and “Inherited and acquired thrombophilia.” Corresponding MeSH terms were used, in addition to searching for titles and abstracts. Inclusion and exclusion criteria were identified. The search was restricted to articles published from February 2012 to 30 April 2023 to capture evidence-based consensus CPGs in those 10 years. The following filters were applied: humans, English, evidence-based guidelines, and practice guidelines. Research articles and reviews of literature were not included. The search results revealed 15 sources, six eligible source CPGs that were assessed for methodological quality by five independent reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument.

This was followed by registration of the adapted guideline on the PREPARE (Practice Guideline Registry for transparency) Platform with the registration number (PREPARE-2023CN908 Three experts in CPG methodology participated in the Guideline Adaptation Group (GAG) Fig. 1.

Six CPGs met an AGREE II (Supplementary file: Fig. 1, Table 1). Overall Assessment score of more than 70% with a score of more than 70% in domain two alone; hence, they were included as source CPGs for the adaptation [1,2,3,4,5,6,7, 20]. Official approvals for adaptation from the selected CPG authors were obtained.

Fig. 1

Phases of the adaptation process

The search results revealed 15 eligible source CPGs that were assessed for methodological quality by six independent reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument [20,21,22,23]. (Supplementary file).

Identification and phrasing of the health questions that needed to be tackled were made using the PIPOH model (Supplementary Table 1). This was followed by the formulation of the adapted recommendations according to the identified health questions. Thirty-two health questions were prioritized (13 for diagnosis, 10 for treatment, and 9 for prevention), for which appropriate recommendations from the adapted CPGs were sought. Evidence levels and grades of recommendations adopted by the EPG were used to classify the quality of evidence and strength of recommendations (Supplementary file Tables 3 and 4) [7]. Five implementation tools supporting the recommendations were adopted and added to the CPG book. The external review process included consultation with three national and one international clinical reviewer and one international guideline methodology reviewer. Their feedback was incorporated in the finalized adapted CPG with the set of implementation strategies and [10] implementation tools, including a Diagnostic algorithm for Pediatric DVTE, an algorithm for the management of venous thromboembolism, an algorithm for the Management Plan of cerebral Sino venous thromboembolism, a table for Common anticoagulant therapies for use in pediatric VTE a health education guidance for patients and families in Arabic., the EPG hematology group will review the need for updates every 5 years and will be guided by the Checklist for the Reporting of Updated Guidelines (CheckUp) Tool [6].

The components of the adapted CPG were further reported using the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension statement for the reporting of adapted CPGs (RIGHT-Ad@pt Checklist) [6] (Supplementary material).

Recommendations

Part I: Diagnosis

What are the clinical features, signs, and symptoms suggestive of venous thromboembolism (VTE) in neonates, children, and adolescents?

The clinical presentation of VTE in children depends on several factors, including the patient's age, anatomic location of the thrombosis, affected organ system(s), characteristics of the thrombus (occlusive vs. nonocclusive), and chronicity (GPS)

Based on the anatomical regions and specific types of venous thromboembolism:

• (a) Upper limb deep vein thrombosis (includes arm veins, the internal jugular vein, and any extension as proximal as the superior vena cava)

  • a. Pain, swelling, and redness of the involved extremity.

• (b) Lower limb deep vein thrombosis with any extension up to the inferior vena cava; pain, limb swelling, inability to walk

• (c) Splanchnic venous thromboembolism: Severe abdominal pain

• (d) Cerebral venous sinus thrombosis: Headache, convulsions (GPS)

• (e) Pulmonary embolism: presentation is based on the patient’s age:

• (f) Pediatric patients may present with nonspecific (i.e., cough, crackles/rales, tachycardia, and persistent tachypnea)

• (g) Adolescents most frequently present with pleuritic chest pain, dyspnea, cough, and hemoptysis (GPS)

• (h) In neonates, acute DVT may present with new-onset thrombocytopenia (GPS)

Specific structures of venous thromboembolism:

• (a) Superior vena cava: SVC syndrome (swelling of the neck and face; dilatation of the superficial collateral venous circulation of the arms, neck, and chest; bilateral periorbital edema; and headaches).

• (b) Inferior vena cava thrombosis: Often silent and non-specific

• (c) Renal vein thrombosis: Presents with thrombocytopenia and hematuria and, if bilateral, can lead to renal insufficiency.

  • i. In the neonatal period, it can also manifest with a palpable flank mass on examination.

  • ii. In older children, it is often associated with nephrotic syndrome and presents with peripheral and periorbital edema.

• (d) Central retinal vein thrombosis. Partial or total visual loss. (GPS)

Specific clinical syndromes:

• (a) Neonatal purpura fulminans: Gangrenous skin lesions mainly in distal extremities with rapidly deteriorating clinical condition.

• (b) Sinusoidal (venous) obstruction syndrome: Massive acute hepatic enlargement with ascites.

• (c) portal vein thrombosis: upper gastrointestinal bleeding with or without splenomegaly. (GPS)

What is the initial evaluation for children and adolescents presenting with thrombosis?

Laboratory investigations

Acute venous thromboembolism

Laboratory investigations are required to aid in the exclusion of systemic disorders in children presenting with a suspected VTE. (Strong) (Low) [3, 4].

• a) Hematology investigations (full blood count, clotting screen) and renal function should be undertaken to confirm safe baselines before anticoagulation. (Strong) (Low)

• b) We suggest testing for PNH in patients with thrombosis at unusual sites and abnormal haematological parameters (i.e., cytopenia and abnormal red cell indices) or evidence of hemolysis (i.e., raised lactate dehydrogenase, bilirubin, and reticulocyte count). (Conditional) [2].

• c) We recommend testing for the myeloproliferative neoplasms (MPN) panel (including JAK2 V617F, JAK2 exon 12, CALR, MPL mutation analysis) in patients with thrombosis at unusual sites and with full blood count abnormalities suggestive of a myeloproliferative neoplasm. (Strong) [2].

• d) Screening for antiphospholipid antibodies is recommended following unprovoked VTE because this may alter management, including choice of antithrombotic therapy. (Strong) [2].

• e) Screening for antiphospholipid antibodies is suggested in patients with VTE provoked by a minor risk factor, as this may alter management, including choice of antithrombotic therapy. (Strong) [2].

Heritable and acquired thrombophilia

Routine testing for heritable thrombophilia is only for recurrent episodes of VTE. (Strong) (Moderate) [3, 4].

Purpura fulminant (PF)

• a) Neonates and children with congenital PF should be tested urgently for protein C and S deficiency (Strong) (Moderate) [3, 4].

• b) Children with early-onset spontaneous thrombotic events should be screened for antithrombin (AT) deficiency. (Strong) (Low) [3, 4].

Radiological

Based on the anatomical site of venous thromboembolism.

• 1. CVL and non-CVL-related VTE in the upper limb (UL)

  • a) Ultrasound (US) is recommended for the initial assessment of the peripheral upper limb, axillary, subclavian, and internal jugular veins, but may be relatively insensitive for the detection of central intra-thoracic VTE (Strong) (Moderate) [3, 4].

  • b) Contrast MRV is recommended for assessing the central veins for VTE (Strong) (Low).

  • c) Multi-detector computerized tomography (CT) venography (MDCT venography) may be considered for the assessment of the central veins if MRV is unavailable. Magnetic resonance imaging (MRI) should always be preferred to CT due to radiation dose considerations in children. (Conditional) (Low) [3, 4].

• 2. CVL and non-CVL-related VTE in the lower limb (LL)

  • a) Doppler US is recommended to assess the LL venous system for VTE. (Strong) (Moderate)

  • b) If the US is normal and the clinical suspicion of VTE remains high, this should be repeated after a week to assess for proximal progression of any calf vein thrombus (Strong) (Low)

  • c) MRV should be considered in children with suspected proximal extension of femoral VTE. (Conditional) (Low) [3, 4].

  • d) Patients presenting with bilateral lower limb DVTE should have their inferior vena cava (IVC) imaged to exclude IVC thrombosis. (Strong) (Moderate) [3, 4].

• 3. For blocked central venous lines

  • a) A chest X-ray is recommended to visualize the CVL position. (Conditional) (Low)

  • b) Doppler US, conventional venography, or contrast-enhanced MRV may be required to exclude large vessel thrombosis. (Conditional) (Low) [3, 4].

• 4. Splanchnic venous thromboembolism:

  Doppler US for mesenteric veins or abdominal CT angiography (Conditional) (Low)

• 5. Cerebral venous sinus thrombosis:

  Urgent brain MRI, including T2* imaging and MRV, to detect both intraparenchymal hemorrhage and sinus thrombosis. (Strong) (Moderate) [3, 4].

• 6. Renal vein thrombosis:

  Pulmonary embolism:

  • a) If available, isotope lung scanning may be considered as the initial imaging investigation, provided the chest X-ray is normal and there is no significant concurrent cardiopulmonary disease. Otherwise, CT pulmonary angiography (CTPA) is recommended as the initial imaging modality for suspected PE. (Strong) [3, 4].

  • b) Pulmonary magnetic resonance angiography (MRA) should be considered as an alternative to CTPA when iodinated contrast injection or radiation is a significant consideration. (conditional) [3, 4].

• 7. Sinusoidal (venous) obstruction syndrome:

  Doppler US, MRV, to detect both intraparenchymal hemorrhage and sinus thrombosis. (Strong) (Moderate) [3, 4].

Inherited thrombophilia

What are the clues in history and examination that suggest inherited thrombophilia in children and adolescents presenting with thrombosis?

• • a) Unprovoked thrombosis at an early age

  • b) Recurrent episodes of thrombosis or thrombophlebitis

  • c) Strong family history of thrombosis or thrombotic events, especially at an early age (< 45 years)

  • d) Thrombosis at multiple or unusual locations, including in the cerebral and jugular

  • e) Migratory episodes or diffuse forms of thrombotic events

  • f) Severity out of proportion to any recognized known stimulus for thrombosis

  • g) Unexplained neonatal thrombosis

  • h) Skin necrosis, particularly if on coumarins or warfarin

  • i) Unexplained, prolonged, activated partial thromboplastin time

  • j) Patients with idiopathic thrombocytopenia, SLE, or recurrent thrombosis, including deep venous thromboembolism.

• What is the indication of thrombophilia screening in children with malignancy?

  The presence of any of the following risk factors in addition to any signs of thrombosis is an indication of thrombophilia screening (conditional) (Moderate) [5].

  • a) Patient-related factors

    Age >10 years (particularly adolescents)

    Inherited thrombophilia

    Personal or family history of VTE

    Obesity

    Immobilization

    Concurrent infection

  • b) Disease-related factors

    Presence of pulmonary/intrathoracic/pelvic disease

    Sarcomas (rhabdomyosarcoma, Ewing sarcoma, osteosarcoma)

    Acute promyelocytic leukemia

    Acute lymphoblastic leukemia

    Lymphomas

  • c) Treatment-related factors

    Major surgery.

    Use of CVLs

Induction chemotherapy for ALL with concurrent administration of corticosteroids and asparaginase (conditional) (Moderate).

Routine thrombophilia screening is not recommended outside the context of large, well-conducted prospective studies intended to assess the impact of prothrombotic defects in modern treatment protocols. (Strong) (Moderate) [5].

• What is the proper timing for tests required to exclude inherited thrombophilia in children and adolescents presenting with thrombosis?

Testing for deficiencies of physiological anticoagulants should be performed only after 3 months of anticoagulation for acute thrombosis. (Conditional) (Moderate) [2].

Part II: Treatment and therapeutic monitoring of venous thromboembolism.

• 1. What is the initial medical treatment plan for pediatric patients with peripheral deep venous thromboembolism/pulmonary embolism (DVTE/PE)?

  • a) Using anticoagulation in pediatric patients with symptomatic DVTE or PE (Strong) (Very low) [6].

  • b) For an asymptomatic patient with proven DVT/PE, the use of anticoagulation is conditional(case-by-case decision) (Conditional) (Very low) [6].

  • c) Using either low-molecular-weight heparin or vitamin K antagonists in pediatric patients with symptomatic DVTE or PE (Conditional) (Very low) [6].

• 2. What are the indications for the use of thrombolysis in childhood VTE/PE?

  • a) The use of thrombolytic therapy is not indicated for the majority of children with VTE but should be considered in the presence of extensive thrombosis, particularly those involving the pelvic veins, SVC, IVC, or intracardiac sites (Strong) (Low) [3, 4].

  • b) Anticoagulation alone is preferred over using thrombolysis followed by anticoagulation in pediatric patients with sub-massive PE. (Conditional) (Very low) [6].

  • c) Using thrombolysis followed by anticoagulation in pediatric patients with PE with hemodynamic compromise. (Conditional) (Very low) [6].

• 3. What are the types and duration of anticoagulation recommended for the treatment of children with VTE/PE?

  • a) Standard of care anticoagulants are UFH, LMWH, AND VKA

    • i. Both UFH and LMWH act by potentiating the inhibitory effects of endogenous antithrombin on several coagulation factors. UFH is mainly given in critically ill patients due to its short half-life, has an available antidote, and non-renal clearance. LMWH is the preferred initial anticoagulant agent because it is administered subcutaneously, allowing for outpatient management and requiring less monitoring. VKA is given for Children with enteral feeding. Preferably not given in neonates and young infants. Bridging with LMWH is needed. [6]

    • ii. Dosing and route of administration (appendix 1)

  • b) Using anticoagulation for < 3 Months in pediatric patients with provoked DVTE or PE (Conditional) (Very low) [6].

  • c) Using anticoagulation for 6 to 12 months in pediatric patients with unprovoked DVTE or PE (Conditional) (Very low) [6].

  • d) Lifelong use of anticoagulants for children with recurrent idiopathic VTE and antiphospholipid syndrome. (Conditional) (Low) [6].

  • e) Anticoagulation should be initiated with low molecular weight heparin (LMWH), followed by warfarin (INR 2.5) or continuing LMWH. (Strong) (Moderate) [6].

  • f) Unfractionated heparin (UFH) may be used for initial therapy where rapid reversal of anticoagulation may be required. (Conditional) (Very low) [6].

  • g) Ongoing therapy with LMWH may be preferable in infants under 1 year of Age. (Conditional) (Very low) [6].

  • h) Initial treatment with UFH or LMWH for at least 5 days.

  • i) For ongoing therapy, we recommend LMWH or UFH. For patients in whom clinicians will subsequently prescribe VKAs, we recommend beginning oral therapy as early as day 1 and discontinuing UFH/LMWH on day 6 or later than day 6 if the INR has not exceeded 2.0 compared with no therapy. (Strong) (Moderate) [7].

• 4. What are the indications for the use of direct oral anticoagulants (DOACs) in neonates and children with thrombosis?

  Considerations for initiating DOACs for the treatment of pediatric VTE.

  • a) Stable patient (unlikely to need an urgent procedure)

  • b) Tolerating good oral intake or on full nasogastric feeds

  • c) Adequate renal and hepatic function

  • d) Unlikely to have antiphospholipid antibody syndrome

  • e) ≥ 5 days of parenteral anticoagulation

  • f) No drug interactions (consult clinical pharmacy)

  • g) For neonates: Gestational age > 37 weeks and weight > 2.6 kg. (GPS)

• 5. How do we monitor the efficacy of anticoagulation in children with thrombosis?

  (Appendex 1).

• 6. What is the initial management of Rt atrial thrombosis in neonates and children?

  • a) Using anticoagulation in pediatric patients with right atrial thrombosis. (Conditional) (Very low) [6].

  • b) Not using thrombolysis or surgical thrombectomy followed by standard anticoagulation but using anticoagulation alone in pediatric patients with right atrial thrombosis (Conditional) (Very low) [6].

• 7. What is the management plan for pediatric patients with central venous access device (CVAD)-related thrombosis?

  • a) No removal of a functioning CVAD in pediatric patients with symptomatic CVAD-related thrombosis who continue to require venous access. (Conditional) (Very low) [6].

  • b) The functioning CVAD can be maintained in pediatric patients who have symptomatic CVAD-related thrombosis with worsening signs or symptoms despite anticoagulation and who continue to require venous access. (Conditional) (Very low) [6].

  • c) Removal of the non-functioning or unneeded CVAD in pediatric patients with symptomatic CVAD-related thrombosis. (Strong) (Very low) [6].

  • d) Delayed removal of a CVAD until after initiation of anticoagulation (days) rather than immediate removal in pediatric patients with symptomatic CVAD–related thrombosis who no longer require venous access or in whom the CVAD is nonfunctioning (Conditional) (Very low) [6].

• 8. What is the initial medical treatment plan for pediatric patients with cerebral Sinovenous thromboembolism (CSVTE)?

  • a) Using anticoagulation is recommended in pediatric patients with CSVTE without hemorrhage. (Strong) (Very low) [6].

  • b) Using anticoagulation is recommended in pediatric patients with CSVTE with hemorrhage. (Conditional) (Very low) [6].

  • c) anticoagulation alone without preceding thrombolysis is recommended in pediatric patients with CSVTE. (Conditional) (Very low) [6].

• 9. What is the duration of medical treatment for pediatric patients with CSVTE?

  Anticoagulation should be continued for

  • a) Three months if there was a clear and treated precipitating factor, e.g., infection. (Strong) (Very low) [3, 4].

  • b) Six months if there is no identified precipitant. (Strong) (Very low) [3, 4].

  • c) Anticoagulation may need to be continued for longer in patients where there is an ongoing risk factor (e.g., continuing treatment with asparaginase), in those with recurrent idiopathic CVTE, and in those with ongoing symptoms or signs attributable to venous hypertension.

  • d) Duration should be considered on an individual basis. (Conditional) (Very low) [3, 4].

  • e) Re-imaging should be undertaken before stopping anticoagulation in patients with ongoing symptoms attributable to venous hypertension (e.g., headache, vomiting, papilledema, visual obscurations, visual field deficit) or with progressive neurological signs.

  • f) Re-imaging is not required in patients with stable neurological signs unless consideration is being given to extending anticoagulant therapy, in which case it may be helpful to establish whether or not recanalization has occurred. (Conditional) (Very low) [3, 4].

• 10. What is the initial medical treatment for neonates with renal vein thrombosis (RVTE)?

  • a) Using anticoagulation rather than no anticoagulation in neonates with RVTE. (Conditional) (Very low) [6].

  • b) Using thrombolysis followed by standard anticoagulation in neonates with life-threatening RVTE. (Conditional) (Very low) [6].

• 11. What is the type of maintenance medical treatment for pediatric patients with RVTE?

  • a) For unilateral renal vein thrombosis (RVTE) in the absence of renal impairment or extension into the inferior vena cava (IVC), ACCP suggests either (1) supportive care with radiologic monitoring for extension of thrombosis (if extension occurs, we suggest anticoagulation) or (2) anticoagulation with UFH/LMWH or LMWH in therapeutic doses rather than no therapy. (Conditional) (Low) [7].

  • b) For unilateral RVTE that extends into the IVC, ACCP suggests anticoagulation with UFH/LMWH or LMWH (Conditional) (Low) [7].

  • c) For bilateral RVTE with evidence of renal impairment, ACCP suggests anticoagulation with UFH/LMWH or initial thrombolytic therapy with tissue plasminogen activator (tPA) followed by anticoagulation with UFH/LMWH (Conditional) (Low) [7].

• 12. What is the duration of medical treatment for pediatric patients with RVTE?

  • a) For unilateral renal vein thrombosis (RVTE) in the absence of renal impairment or extension into the inferior vena cava, ACCP suggests a total duration of between 6 weeks and 3 months rather than shorter or longer durations of therapy (Conditional) (Low) [7].

  • b) For unilateral RVTE that extends into the IVC, ACCP suggests anticoagulation with UFH/LMWH or LMWH for a total duration of between 6 weeks and 3 months (Conditional) (Low) [7].

• 13. What is the initial medical treatment of portal vein thrombosis (PVTE) in children and neonates?

  • a) Using anticoagulation therapy in pediatric patients with PVTE with occlusive thrombus, post-liver transplant, and idiopathic PVTE. (Conditional) (Very low) [6].

  • b) No anticoagulation for pediatric patients with PVTE with nonocclusive thrombus or portal hypertension (Conditional) (Very low) [6].

  • c) In children who will not be anticoagulated, follow-up monitoring is important because the extension of thrombus or organ dysfunction may require reconsideration of treatment options. (Conditional) (Very low) [6].

• 14. What is the initial anticoagulant treatment plan for children with cancer and VTE?

  • a) Children with VTE unrelated to CVLs should receive anticoagulation for an initial period of 3 months. (Strong) (Low) [2].

  • b) Continuation of treatment beyond 3 months should be considered in patients with active cancer or other ongoing risk factors. (Conditional) (Low) [2].

  • c) Children with cancer who are found to have incidental VTE should be considered for systemic anticoagulation as per protocols for symptomatic disease. However, if the thrombosis is solely CVL-related, then it is reasonable to withhold anticoagulation initially and monitor the patient. (Conditional) (Low) [2].

• 15. What is the best anticoagulant for children with cancer with VTE?

  • a) LMWH is the anticoagulant of choice for VTE in children with malignancy (Conditional) (Low) [2].

  • b) Unfractionated heparin can also be used for the initial treatment of established VTE for patients with cancer when LMWH or direct oral anticoagulants are contraindicated or not available. (Conditional) (Low) [2].

  • c) Routine antithrombin supplementation is not recommended during LMWH or unfractionated heparin (UFH) anticoagulation. (Conditional) (Low) [2].

  • d) Routine measurement of peak anti-Xa activity, with a target range of 0.5–1.0 units/mL, is recommended for children receiving LMWH. (Conditional) (Low) [2].

  • e) Coagulopathies should be corrected, and fibrinogen levels maintained above 1 g/l in children on anticoagulant therapy. (Conditional) (Low) [2].

• 16. What is the management plan for the use of anticoagulants in children with cancer during the period of thrombocytopenia?

  • a) Therapeutic anticoagulation may be continued while the platelet count is > 50 × 10⁹/l.(Strong) (Moderate) [2].

  • b) Outside of these scenarios, an alternative approach of reducing the anticoagulation dose to 50% when the platelet count is between 25 and 50 × 109/l and temporarily interrupting anticoagulation when < 25 × 109/l could be considered. (Conditional) (Low) [2].

• 17. What is the management plan for the use of anticoagulants in children with cancer around invasive procedures?

  • a) For children with normal renal function on LMWH, the last therapeutic dose should be given at least 24 h before an invasive procedure, and the last prophylactic dose at least 12 h before an invasive procedure. LMWH should be restarted no sooner than 4–6 h after a procedure. (Strong) (Moderate) [2].

  • b) For children on warfarin, the last dose should be given 4–5 days before an invasive procedure. Bridging anticoagulation with LMWH when the International Normalized Ratio (INR) becomes sub-therapeutic will be required for individuals within 1 month of a VTE. This should also be considered for up to 3 months after a VTE in those judged to be at particularly high risk of recurrence. (Conditional) (Moderate) [2].

• 18. What is the treatment plan for children with cancer during Re-exposure to asparaginase following a thrombotic event?

  • a) Further doses of asparaginase may be administered following an asparaginase-related VTE, provided they are covered by prophylactic or therapeutic anticoagulation. (Strong) (Moderate) [2].

  • b) Such anticoagulation should be continued for at least 3 weeks following each dose of pegylated asparaginase. (Strong) (Moderate) [2].

  • c) We suggest that re-exposure to asparaginase is delayed until symptoms of the initial VTE have improved and, in the case of CVTE, repeat imaging demonstrates stabilization or improvement of the thrombosis. (Conditional) (Low) [2].

• 19. What is the Treatment of VTE recurrence in patients with cancer under anticoagulation?

  In the event of VTE recurrence, three options can be considered:

  • a) Increase LMWH by 20–25% or switch to direct oral anticoagulants;

  • b) For direct oral anticoagulants, switch to LMWH

  • c) for vitamin K antagonists, switch to LMWH or direct oral anticoagulants (guidance based on evidence of very low quality and an unknown balance between desirable and undesirable effects). (GPS) [2].

• 20. How to Treat Bleeding occurring in children on anticoagulation?

  • a) Use of heparin antagonist (protamine sulfate). The dose is based on the time elapsed since the last heparin dose (Table 3 in Appendix)

  • b) Reversal of anticoagulation drugs (Appendix)

Prevention

• 1. When should hospitalized patients be evaluated for risk of thrombosis or bleeding?

  All hospitalized patients 6 months of age or older should be evaluated for both bleeding and VTE risk within 24 hours of admission, upon transferring level of care, and periodically during hospital stay (every 48-72 hours). (Strong) (Low) (GPS) [1].

• 2. How to evaluate thrombosis risk in hospitalized patients?

  VTE Risk Factors:

  • a) Acute conditions

    • i. Reduced mobility longer than 48 h

    • ii. Central venous access device

    • iii. Active infection

    • iv. Major trauma or burn

    • v. Major surgery

    • vi. Critically ill

    • vii. Hypoalbuminemia

    • viii. Blood transfusion within the previous 48 h

  • b) Chronic medical condition

    • i. Post-pubertal and/or age 12 years or older

    • ii. Autoimmune disorders associated with thrombosis

    • iii. Thrombophilic condition

    • iv. Active malignancy

    • v. Obesity

  • c) Historical factors

    • i. Asparaginase therapy within the previous 30 days

    • ii. Recent surgery within the past 30 days

    • iii. History of thrombosis

    • iv. Family history of VTE in a 1 st degree relative < 40 years old at the time of clot. (GPS)

  Risk Factor Stratification definitions: (Table 1).

  • a) Low VTE risk:

    No altered mobility and 0-2 risk factors

  • b) Moderate VTE risk:

    No altered mobility and 3–4 risk factors.

    Altered mobility and 0–2 other risk factors.

  • c) High VTE risk:

    No altered mobility and ≥ 5 risk factors.

    Altered mobility and ≥ three other risk factors (GPS) [1]

• 3. How to evaluate bleeding risk with the use of anticoagulation DVT prophylaxis in hospitalized patients?

  • d) If a patient meets at least one of the criteria of the “anticoagulation prophylaxis NOT Recommended” list, avoid anticoagulation prophylaxis as the risk outweighs the benefit. (Strong) (Very low) [1] (Table 2).

  • e) If the patient meets at least one of the following criteria in the “Consider Avoiding Anticoagulation Prophylaxis” list, consider avoiding anticoagulation (Conditional) (Very low) [1] (Table 2).

  • f) Consider consulting hematology for recommendations if the patient is considered at high risk for VTE but also has a high bleeding risk.

    (GPS) [1].

• 4. What are the measures used for thromboprophylaxis?

  • a) Non-pharmacologic (physical methods)

    • i. Maintaining good hydration and early mobilization whenever possible. (GPS) [3, 4].

    • ii. Should be considered in older children and adolescents who are at increased risk of VTE. (Strong) (Low) [3, 4].

    • iii. physical methods may be helpful with high risk of bleeding by anticoagulant-based prophylaxis. (Strong) (Low) [3, 4].(Table 1)

    • iv. Mechanical prophylaxis methods: sequential compression device (SCD), graduated compression stockings (GCS), all should be done by consulting physical therapy and/or occupational therapy to assist with the patient’s movement. (GPS) [3, 4].

Contraindications of mechanical prophylaxis

• i. The extremity has an acute fracture.

• ii. The extremity has peripheral IV access.

• iii. Skin condition affecting extremities (i.e., dermatitis, burn, etc.).

• iv. Unable to achieve a correct fit due to patient size.

• v. Lower extremity peripheral arterial insufficiency. (Strong) (Low) [1].

• b) Pharmacological prophylaxis (Anticoagulation Prophylaxis): (Appendex 1)

  There is no evidence for using aspirin for VTE prophylaxis in children. (conditional)(low) [3, 4].

  Children, particularly adolescents, with multiple risk factors for VTE should be considered for thromboprophylaxis with LMWH. (Conditional) (Low) [3, 4].

• 5. What is the duration of thromboprophylaxis in patients with hereditary thrombophilia?

  • a) A positive thrombophilia evaluation is not a sufficient basis to offer extended anticoagulation following an episode of provoked VTE. (GPS)

  • b) A negative thrombophilia evaluation is not a sufficient basis to stop anticoagulants following an episode of unprovoked VTE in a patient with low bleeding risk and willingness to continue therapy. (GPS)

  • c) Heterozygosity for FVL or PGM does not increase the predicted risk of recurrence after unprovoked VTE to a clinically significant degree. (GPS)

  • d) A family history of VTE confers an excess risk of thrombosis: relatives should be counseled regarding the use of prophylaxis in high-risk situations. (GPS)

• 6. What are the drugs to be avoided in a child with risk factors for thrombosis?

  Especially in high-risk groups for VTE, physicians should be cautious when using some drugs that may alter the balance between different coagulation factors and some drugs that can increase blood viscosity, such as hormones steroid base and corticosteroids and intravenous immunoglobulines (GPS).

• 7. How to monitor the effectiveness of prophylactic anticoagulants?

  • a) Complete blood count (CBC): Obtain baseline CBC within 48 h of initiation of enoxaparin or heparin(Strong) (Very low) [1].

  • b) International normalized ratio (INR): A target INR of 2.5 is generally required for achieving good hemostasis for childhood VTE treated by Vitamin K antagonist (GPS) [1].

  • c) Anti-Xa: You may consider checking the anti-Xa level if the patient experiences active bleeding or has evidence of renal dysfunction while receiving enoxaparin. (Conditional) (Very low) [1].

    • a Routine anti-Xa levels are not recommended with enoxaparin, heparin, or rivaroxaban at prophylactic doses. (GPS) [1].

• 8. What is the role of nutrition in the prevention of thrombosis?

  • Good hydration maintains the blood volume and improves viscosity. (GPS)

  • Obesity is a risk factor for many diseases, including heart disease and thrombosis; therefore, maintaining optimal growth and preventing obesity is recommended. (GPS)

Table 1 Prophylaxis recommendation based on VTE risk

Table 2 Recommendations for specific factors associated with increased bleeding risk:

Discussion

This CPG was prepared to provide practical consensus recommendations for the management of thrombosis in children and adolescents in Egypt. We followed an established methodology to systematically review the literature and applied the AGREE II tool to assess the quality of the adapted guidelines. Lastly, the adapted CPG recommendations are released to identify masked disease areas and areas of uncertainty to aid prospects [18].

There is a lack of evidence to support strong recommendations for various management approaches. Most of the adapted CPGs recommended clinical and radiological assessment as a broad base for diagnosis, and specific laboratory assessment at the initial diagnosis is a debated process. According to the adapted clinical guidelines, clinical symptoms and signs are the most important step in diagnosis. Given the lack of strong evidence for most of the recommendations in the pediatric age group, future research should focus on providing rigorous evidence on these management options in this vulnerable age group.

Further evaluation of this ADAPT guideline must be conducted to measure the outcome regarding VTE incidence, bleeding complications, adherence to guidelines, and healthcare costs. This could be through national survey programs annually targeting the healthcare providers.

Strengths and Limitations

To our knowledge, this adapted guideline is the first to provide high-quality evidence about the management of thrombosis in children and adolescents in resource-limited countries like Egypt, providing applicable implementation tools.

The current analysis has a few limitations. The use of the AGREE II tool is relatively recent, and older CPGs may not have adopted recently developed standards, which may skew the findings. Specifically, the practice of involving stakeholders, including lay consumers, in CPG development, as well as active guideline implementation in clinical practice, is relatively new and usually absent in older CPGs. The study was unable to assess the quality and confidence in linked evidence to guideline recommendations, as different evidence grading systems were used in different CPGs. This limited the ability to provide an in-depth analysis of the current evidence gap.

This adapted CPG provides consensus recommendations and implementation tools for the management of thrombosis in children and adolescents in Egypt. Current CPGs on the diagnosis and management of thrombosis in children and adolescents vary in their scope and methodological quality. Moreover, there is a lack of strong evidence to support most of the adapted recommendations in the current CPGs. Future research should aim at doing high-quality studies to provide sufficient evidence in the field of pediatric thrombosis.

Quality of Source CPGs: The reliance on existing CPGs means that the adapted CPG is limited by the quality of the source material.

Generalizability: The CPG is specifically tailored to the Egyptian healthcare context, which may limit its generalizability to other settings.

Conclusions

The adaptation of CPG recommendations is a good and valid alternative to de novo developing a CPG for thrombosis diagnosis, treatment, and prevention in pediatric age groups, especially given the lack of relevant, high-quality systematic reviews and randomized controlled trials in the Egyptian context.

Challenges and future suggestions

This adapted guideline addresses pediatric venous thromboembolism and is designed to systematically assist pediatricians in Egypt in managing venous thrombotic disorders, considering the limited resources available. Arterial thrombosis, which is not common in children, was outside the scope of these revised guidelines. Additional recommendations are required to handle pediatric arterial thrombosis.

Appendix

• 1. Anticoagulation drugs

  • a UFH is usually initiated with a loading dose of 75-100 U/kg administered intravenously over 10 minutes. After a loading dose of about 100 IU/kg, a maintenance dose (28 U/kg/h) in neonates and (20 U/kg/h) in older children to achieve aPTT values (78–200 s) [24].

    • a) For VKA: warfarin: 0.2 mg/kg orally

      >5 years: 0.15 mg/kg orally once daily

      1–5 years: 0.10 mg/kg orally once daily

      >5 years: 0.05 mg/kg orally once daily

      Consider Check INR to target 2-2.5 of normal value (GPS) [25]

  • b Low molecular weight heparin (LMWH)

    • a) Enoxaparin is the preferred pharmacologic prophylaxis agent for pediatric patients. (Strong) (Low) [1].

    • b) The use of subcutaneous (SQ) injections is preferred due to the lack of evidence of intravenous administration in the prophylactic setting. (GPS) [1].

    • c) Avoid enoxaparin or heparin if the patient has hypersensitivity to enoxaparin, heparin, pork products, or any component of the formulation. (Strong) (Low) [1].

    • d) LMWH is given SC twice daily as follows:

      • i. Neonates: A starting dose of 2 mg/kg twice daily in preterm, and 1.7 mg/kg twice daily in term neonates is suggested

      • ii. For children: starting dose of 1 mg/kg twice daily.

    • e) Target anti-Xa activity was measured four hours following the subcutaneous injection. Prophylactic 0.1–0.4 u/ml. (Strong) (Low) [1].

  • c Warfarin

    Initial loading dose of 0.2 mg/kg p.o. for 2 d.

    • Subsequent dose adjustments should be based on the INR result.

  • d Rivaroxaban

    • f) Rivaroxaban, an oral anticoagulant with FDA approval in the pediatric population, may be considered for prophylaxis in patients with high VTE risk if appropriate, based on patient characteristics. (Conditional) (Low) [1].

    • g) Rivaroxaban may be used based on individual considerations.

    • h) Only use rivaroxaban in infants weighing at least 2.6 kg whose serum creatinine is less than the 97.5^th percentile and children or adolescents with eGFR > 50 mL/min/1.73 m².

    • i) Patients should receive at least five days of parenteral anticoagulation and at least ten days of enteral feeding before starting rivaroxaban for VTE prophylaxis. (Strong) (Low) [1].

• 2. Monitoring the efficacy of anticoagulation in children with thrombosis.

  • a) Therapeutic UFH in children is titrated to achieve an activated partial thromboplastin time (aPTT) 1.5-2.5 of the normal range (a target range of anti-Xa activity of 0.35 to 0.7 units/mL) if available (Conditional) (Low) [7].

  • b) For neonates and children receiving either once- or twice-daily therapeutic LMW, that the drug be monitored to a target anti-Xa activity range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection. (Conditional) (Low) [7].

  • c) For children receiving vitamin K antagonists (VKAs), the drug should be monitored to a target international normalized ratio (INR) of 2.5 (range, 2.0-3.0 (Conditional) (Low) [7].

• 3. Reversal of the standard of car anticoagulation drugs

  • 1. Reversal of heparin therapy (Table 3)

  • 2. For LMWH reversal: the typical dose of protamine is 1 mg per 1 mg (100 U) of enoxaparin administered within the previous 8 hours, with a maximum single dose of 50 mg [10]. If greater than 8 hours have elapsed since enoxaparin administration, a dose of 0.5 mg of protamine per 1 mg (100 U) of enoxaparin is suggested. For ongoing bleeding, an additional dose of 0.5 mg for every 1 mg of enoxaparin can be considered [7, 11, 12]. (GPS)

  • 3. Reversal of warfarin with Vitamin K: Vitamin K can be given p.o. or i.v., dosing regimens vary, but doses of 30 µg/kg or 0.3–5 mg have been reported to be effective (GPS) [1, 26].

Table 3 Reversal of heparin therapy